Why Are Cancer Cells Within the Same Tumor Different?
A tumor is not a mass of identical cells. As a cancer grows, its cells pick up new changes and are shaped by the conditions around them, which are not the same in every part of the tumor. The result is a mix of cell groups that can grow at different speeds, spread differently and respond differently to treatment.
By Chris Morais, MSc, MPhil, PhD
Published
Cancer cells in one tumor come from the same starting cell, but they do not stay the same. As they divide, some cells gain new gene changes, some switch genes on or off, and some end up in areas with less oxygen or food. These differences, called tumor heterogeneity, help explain why one treatment may not kill every cancer cell.
- What Is Tumor Heterogeneity?
- How Can One Cancer Develop Many Different Groups of Cells?
- How Does Natural Selection Operate Inside a Tumor?
- Can Cancer Cells Differ Without Having Different DNA Mutations?
- How Can Different Parts of a Tumor Have Different Conditions?
- Can Cancer Cells Differ in How Quickly They Divide?
- Can Cancer Cells Within One Tumor Respond Differently to Treatment?
- Can the Cells in a Tumor Change Over Time?
- Are Primary and Metastatic Tumors Genetically Identical?
- Why Does Tumor Heterogeneity Make Cancer More Difficult to Study and Treat?
- Frequently Asked Questions
What Is Tumor Heterogeneity?
Tumor heterogeneity means that the cancer cells inside a single tumor are not all the same[1]. Some cells carry gene changes that others do not. Some divide faster, move more easily or survive treatment better than their neighbors.
Scientists use two related terms[1]:
- Intratumor heterogeneity. Differences between cancer cells within the same tumor, or between the first tumor and the tumors it later forms in other parts of the body. This is the main subject of this article.
- Intertumor heterogeneity. Differences between the tumors of different people, even when they have the same type of cancer.
The differences inside a tumor exist in both place and time[1]. One part of a tumor can contain different cells from another part. The same tumor can also contain different cells at different stages of the disease.
These differences are very common. Studies covering many types of cancer have found signs of more than one group of cancer cells in about 95% of tumor samples[4].
The table below summarizes the main reasons cancer cells in one tumor differ. Each is explained in the sections that follow.
| Source of difference | What changes | Example |
|---|---|---|
| New gene mutations | The DNA sequence | One group of cells gains a mutation that helps it grow faster |
| Epigenetic changes | Which genes are switched on or off, with no change in the DNA sequence | Some cells silence a gene that others keep active |
| Local conditions | Oxygen, nutrients and acidity around the cells | Cells near a blood vessel get more oxygen than cells far from it |
| Division speed | How often a cell divides | Some cells divide often, while others rest |
| Pressure from the immune system or treatment | Which cells survive and multiply | Cells that resist a drug are left behind after treatment |
How Can One Cancer Develop Many Different Groups of Cells?
One cancer develops many groups of cells because its cells keep gaining new changes as they divide, and each cell passes its changes on to the cells it produces[1],[2].
Most cancers begin with a single cell that has gained harmful gene changes (see How Do Genetic Changes Turn a Normal Cell into Cancer?). That cell divides into two, those two divide into four, and so on. At first, all the cells carry the same gene changes.
This does not last. Cancer cells often copy and repair their DNA less accurately than normal cells, so new changes keep appearing as they divide. A new change that appears in one cell is passed on only to the cells that come from it. Over many rounds of division, the tumor fills with separate groups of cells, each with its own set of changes[2].
How Do New Genetic Changes Create Cancer Cell Subclones?
A new genetic change creates a subclone when it appears in one cancer cell and that cell then divides to form a group of cells that all carry the change[1].
A clone is a group of cells that all come from one cell. In cancer, the first cancer cell gives rise to the whole tumor. A subclone is a smaller group within the tumor that comes from a later cell that gained an extra change.
This gives two kinds of genetic changes in a tumor[1],[2]:
- Shared changes. These were present in the first cancer cell, so they are found in every cancer cell in the tumor.
- Later changes. These appeared after the cancer had started growing, so they are found only in the subclone that came from the cell where they first happened.
The process does not stop with one subclone. A cell inside a subclone can gain yet another change and start a new, smaller subclone of its own. Different subclones can also gain different changes at the same time. Research shows that cancers commonly grow in this way, splitting into several groups that develop side by side, rather than in a single line where each new group replaces the one before it[2].
How Does Natural Selection Operate Inside a Tumor?
Natural selection operates inside a tumor when some cancer cells survive and multiply better than others under the conditions they face, so their subclones become more common over time[2].
This is the same basic process that shapes living things in nature. It needs two things. First, there must be variation, which a tumor has because its cells are different. Second, the surroundings must favor some cells over others. Cells that are better suited to their surroundings produce more cells. Cells that are poorly suited grow slowly, stop growing or die[2].
Inside the body, the conditions that favor some cancer cells over others include low oxygen, a shortage of nutrients, acidity and attack by the immune system[4]. Cancer treatment adds another strong pressure. The immune system, for example, tends to kill cancer cells that are easy to recognize and leave harder-to-recognize cells behind (see How Do Cancer Cells Hide from the Immune System?).
Why Do Some Cancer Cell Clones Expand More Than Others?
Some cancer cell clones expand more than others because their changes give them an advantage, such as faster growth, better survival in harsh conditions or the ability to avoid immune attack[2].
A clone with an advantage produces more cells than its neighbors, so over time it makes up a larger share of the tumor. A clone with no advantage may stay small. A clone with a harmful change may die out[2].
An advantage depends on the setting. A change that helps a cell survive with little oxygen gives no benefit in a part of the tumor that has plenty of oxygen. A change that protects a cell from a particular drug gives no benefit until that drug is used[2]. This is why the mix of clones in a tumor can shift when conditions change.
Can Cancer Cells Differ Without Having Different DNA Mutations?
Yes. Cancer cells with exactly the same DNA sequence can still behave differently, because they can differ in which of their genes are switched on or off[1],[3].
Every cell carries thousands of genes, but it uses only some of them at any one time. Two cancer cells with the same DNA can make different proteins simply because they are using different genes. As a result, they can differ in how fast they grow, how they make energy and how well they survive treatment[1].
How Can Epigenetic Changes Create Different Cell Behaviors?
Epigenetic changes create different cell behaviors by changing which genes a cell can use, without changing the DNA sequence itself[3].
"Epigenetic" refers to chemical marks on DNA, and on the proteins that DNA is wrapped around, that help control whether a gene is switched on or off. The best-known mark is DNA methylation, in which small chemical tags are attached to DNA. A gene covered in these tags is usually switched off. When a cell divides, its marks are usually copied too, so the new cells keep the same pattern of active and silent genes[3].
Cells within one tumor can carry different epigenetic patterns. Abnormal epigenetic changes are found in cancers even more often than gene mutations, and they can begin at the earliest stages of the disease[3].
Epigenetic differences are important for three reasons:
- They can change how cells respond to treatment. The epigenetic state of a cancer cell can affect whether it survives a drug[3].
- They can be influenced by the surroundings. Epigenetic marks can be changed by a cell's environment more easily than the DNA sequence can[3].
- They may be reversible. Unlike a mutation, an epigenetic mark can sometimes be removed. Researchers are testing medicines that act on these marks to see whether they can make resistant cancer cells respond to treatment again[3].
How Can Different Parts of a Tumor Have Different Conditions?
Different parts of a tumor have different conditions because the tumor's blood supply is uneven, so some areas receive plenty of oxygen and nutrients while others receive very little[1].
Cells need blood to bring oxygen and food and to carry waste away. Tumors trigger the growth of their own blood vessels, but these vessels are often disorganized and leaky (see Why Do Tumors Need New Blood Vessels? Angiogenesis Explained). As a result, one region of a tumor can be well supplied while a nearby region is short of supplies.
These differences affect the cancer cells living in each area. They also favor different subclones in different regions[4]. So two parts of the same tumor can end up with different mixes of cells.
How Do Oxygen, Nutrients and Acidity Vary Within a Tumor?
Oxygen and nutrients are usually highest in parts of a tumor close to working blood vessels and lowest in parts far from them, while acidity tends to build up where oxygen is low[1],[4].
- Oxygen. Oxygen can travel only a short distance from a blood vessel into tissue. Cells far from a vessel, often in the center of a tumor, can run short of oxygen. This is called hypoxia[1].
- Nutrients. The same cells far from blood vessels also receive less glucose (sugar) and other nutrients[1].
- Acidity. Cells that are short of oxygen rely more on ways of making energy that do not need oxygen[1]. These produce lactic acid, which builds up when blood flow is too poor to carry it away. Acidity is one of the conditions that can favor some cancer cells over others[4].
A common pattern is a well-supplied outer region, where cells divide quickly, and a poorly supplied center, where cells may divide slowly or stop dividing[1].
Can Cancer Cells Differ in How Quickly They Divide?
Yes. Some cancer cells in a tumor divide often, while others divide slowly or rest for long periods without dividing[1].
Several things cause these differences:
- Gene changes. Some subclones carry changes that drive faster division (see Why Do Cancer Cells Keep Growing?).
- Local conditions. Cells with plenty of oxygen and food can divide more often than cells in poorly supplied areas[1].
- Stage of the cell cycle. At any moment, cells are at different points in their cycle of growth and division, which adds to the differences between them[1].
- Resting cells. Some cancer cells enter a resting state, called quiescence, in which they stop dividing but stay alive. Some of these cells have stem-cell-like features and can start dividing again later[1].
Resting cells are important because many cancer treatments work best against cells that are actively dividing. A resting cell may survive a treatment that kills the dividing cells around it[1].
Can Cancer Cells Within One Tumor Respond Differently to Treatment?
Yes. Cancer cells within one tumor can respond very differently to the same treatment, so a treatment may kill most of the cancer cells while a smaller group survives[2],[4].
Cells can survive treatment for several reasons:
- They already carry a resistance change. A small group of resistant cells can be present in a tumor before treatment starts. Even when these cells are rare, they can survive and later cause the treatment to fail[2].
- They lack the drug's target. Many modern cancer drugs act on one particular gene change or protein. If only some subclones carry that change, the drug mainly affects those subclones. For this reason, a single drug may not be enough for a tumor whose cells are genetically mixed[2].
- They are in a protective epigenetic state. Cells with the same DNA can differ in how well they survive a drug because they are using different genes[3].
- They are resting. Cells that are not dividing can survive treatments that target dividing cells[1].
- They are in a hard-to-reach area. Drugs travel through the blood, so cells in parts of a tumor with a poor blood supply may receive less of a drug.
If the surviving cells grow back, the tumor that returns is made mostly of cells like the ones that survived. This is natural selection again, with the treatment acting as the pressure that favors some cells over others[2].
Can the Cells in a Tumor Change Over Time?
Yes. The mix of cells in a tumor changes over time as new changes appear and as changing conditions favor different subclones[1],[2].
A tumor at diagnosis can be quite different from the same tumor later in the disease. New mutations and epigenetic changes keep appearing. As the tumor grows, its blood supply, its oxygen levels and the immune attack it faces also change, so the subclones that do best can change too.
Treatment is one of the strongest causes of change. It removes the cells it can kill and leaves the rest. A subclone that was small before treatment can become the main group of cells afterwards[2]. Because a tumor contains many different cells, it has more options for adapting to these pressures[2].
Some cancer cells can also change their behavior without any new mutation, by switching between different states over time[1]. This ability, called plasticity, gives a tumor another way to adapt.
Are Primary and Metastatic Tumors Genetically Identical?
No. Primary and metastatic tumors share the gene changes that were present when the cancer started, but each can also carry changes that the other does not have[1],[2].
The primary tumor is the first tumor, in the place where the cancer started. A metastatic tumor forms when cancer cells leave the primary tumor, travel through the body and grow in a new place (see How Does Cancer Spread to Other Parts of the Body?).
Because a metastatic tumor grows from cells of the primary tumor, the two share the original changes found in every cancer cell. But a metastasis usually grows from one subclone, not from all the different cells in the primary tumor. Once it settles in its new location, it keeps gaining new changes of its own, while the primary tumor keeps changing separately. Studies have found gene changes present only in the primary tumor or only in the metastases[2].
This can affect treatment. A drug chosen because of a change found in the primary tumor may work less well against a metastasis that lacks that change.
Why Does Tumor Heterogeneity Make Cancer More Difficult to Study and Treat?
Tumor heterogeneity makes cancer more difficult to study and treat because a small sample may not show everything about the cancer, and a treatment that works against some cancer cells may miss others[1],[2].
It makes cancer harder to study. Doctors often learn about a cancer by testing a small piece of tissue, called a biopsy. If the tumor is mixed, one biopsy taken from one place may miss important subclones in other places or in metastases[2]. Where the sample is taken from can affect what it shows[1].
It makes cancer harder to treat. A treatment aimed at one change mainly affects the cells that carry that change[2]. Resistant cells, resting cells and cells in poorly supplied areas may survive and allow the cancer to return[1],[2]. Tumor heterogeneity is considered one of the main reasons why cancer treatments stop working[4].
This does not mean cancer treatment does not work. Many cancers are cured or kept under control for many years with current treatments. Doctors and scientists already use what they know about heterogeneity to plan care, for example by:
- Combining treatments that work in different ways, so that cells that escape one treatment can be reached by another[2].
- Testing more than one sample when possible, to get a fuller picture of the cancer.
- Checking the cancer again over time, so that treatment can be adjusted if the cancer changes.
- Developing new treatments, including medicines aimed at epigenetic changes, that may make resistant cells respond again[3].
Understanding why cancer cells differ is one of the main ways researchers are working to make cancer treatments last longer.
Frequently Asked Questions
Do all cancers have different groups of cells? Most do. Studies covering many types of cancer have found signs of more than one group of cancer cells in about 95% of tumor samples[4]. The amount of variation differs between cancer types and between people.
Does having more differences between cancer cells mean a worse outlook? It may. Tumors with high levels of variation between their cells may be linked to worse outcomes[1]. However, many other things also affect outlook, such as the cancer type, its stage and how it responds to treatment, so the level of variation alone does not predict what will happen to one person.
Are the different groups of cells in one tumor separate cancers? No. The cells in one tumor come from the same starting cancer cell and share its original gene changes[1],[2]. The different groups are subclones of one cancer, not separate cancers.
Are cancer stem cells part of tumor heterogeneity? Yes. Many tumors contain a small group of cells with stem-cell-like features, such as the ability to renew themselves and to rest for long periods[1]. These cells add to the variety within a tumor and may help a cancer survive treatment[1].
Can the same type of cancer behave differently in two people? Yes. Tumors of the same type can differ a great deal between people. This is called intertumor heterogeneity[1]. It is one reason why two people with the same type of cancer may receive different treatments.
Morais C. Why Are Cancer Cells Within the Same Tumor Different? [Internet]. BiologyWithin.com; 2026 Oct 15. Available from: https://www.biologywithin.com/2026/10/why-are-cancer-cells-in-same-tumor-different.html
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- Zhang A, Miao K, Sun H, Deng CX. Tumor heterogeneity reshapes the tumor microenvironment to influence drug resistance. Int J Biol Sci. 2022;18(7):3019–3033.
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